Transcript IBS - AGA - Advances in Inflammatory Bowel Diseases

Evaluating and Treating Pain in IBD
Eva Szigethy MD, PHD
Associate Professor of Psychiatry, University of Pittsburgh
Director, Medical Coping Clinic, Children’s Hospital of Pittsburgh
Director, Visceral Inflammation and Pain (VIP) Center
Division of Gastroenterology, Hepatology, and Nutrition
December 12, 2013
Disclosure
• Sources of Funding
–
–
–
–
CCFA Senior Investigator Award
NIMH R01 Grants
American Psychiatric Press Inc., Book Editor
Merck- Consultant, Advisory Board
• All medication suggestions in this presentation
are off-label uses unless noted otherwise.
Abdominal pain is common in IBD
Of adults with IBD, 20% consume up to 80% of medical
costs. Chronic pain and depression are key factors
Binion et al., 2010
Relationship between pain and telephone
encounters in adults with IBD
Ramos Rivers 2013
Multiple Factors to Consider for Causes of
Pain in IBD
•
•
•
•
•
•
Inflammation
Anatomical- strictures/adhesions/fistulas
Bacterial overgrowth- small intestine
Neurobiological/Psychological
Psychosocial
Genetics
Bielefeldt et al., Inflamm Bowel Dis 2009; Srinath et al., Ther
Advances in Gastro 2012; Camilleri N Engl J Med 2012
IBD-IBS
• 30-80% of adults with inactive IBD had irritable
bowel syndrome (IBS) symptoms
• Self-reported pain in 45%-100% pediatric patients
with IBD
• 10-40% with IBS
• Over half depressed
Simren et al., Am J Gastroent 2002 ; Minderhound et al., Dig Dis Sci 2004; Farrokhyar et al., Inflamm Bowel
Dis 2006; Ansari et al., Eur J Gastro Hepatol 2008; Zimmerman et al., Inflamm Bowel Dis 2012, Crandall et
al., J Ped Gastro & Nutr 2007
Greenley et al., J Ped Psychol 2012
Unrecognized inflammation in adults with
quiescent IBD
Crohn’s Disease
Ulcerative
Colitis
Keohane et al., Am J
Gastroenterol 2010
Influences on Visceral Sensitization
 Stress
 Abnormal inputs
Repetitive bowel stimulation
 Acute inflammation
Infection
IBD (mild or in remission)
 Neurological trauma
Operations
Invasive procedures
Zighelboim J, Dig Dis & Sci 1995; 40:819
Drossman DA et. al., Gastroenterology 2002
The brain can amplify the pain from the gut
● Pain involves both the
gut and brain
● Acute GI pain usually
results from injury to the
gut (e.g., active disease
or infection)
● Chronic GI pain can
result from the gut
(visceral
hypersensitivity), brain
(central hypersensitivity),
or both
ABDOMINAL PAIN
Psychological
Depression and anxiety in adult and pediatric IBD
 Mood disorders linked to persistent pain in
quiescent IBD



Increased worrying, limited coping ability, somatization
Mechanisms still unclear
Szigethy et al. J Am Acad Child Adolesc Psychiatry. 2004; Fuller-Thomson,
Sulman. IBD 2006; Farrokhyar et al. IBD 2006; Srinath et al. DDW 2011
(Abstract); Graff et al IBD 2009
ABDOMINAL PAIN
Psychosocial

Life stressors ~ coping  pain perception in IBD

Early life trauma linked to visceral hypersensitivity

Chronic stress reactivation risk
Ross et al. JPGN 2011
Drossman. Am J Gastroenterol 2011
Engstrom J Am Academ Child Adolesc Psych 1991
Levenstein et al. Am J Gastroenterol 2000
Components of Pain History
(Clinical Manual of Pain Management in Psychiatry, R. Leo, APPI 2007)
Somatic
Onset/Duration
Location
Quality
Intensity
Psychological
Mood/Affect
Cognitive
Coping
Psychiatric Illness
Associated
features
Aggravating
factors
ABD
Alleviating factors
PAIN
Social
Impact on
relationships
Capacity for
intimacy/sexuality
Activities of daily
living
Educational
Vocational
Pain is a modifiable experience
Psychosocial Context
•
•
•
•
•
•
•
Pain Experience
Pain beliefs
Cultural
Expectation
Conditioning
Social support
Stress
Sleep
Cognitions
• Hypervigilance
• Attention
• Catastrophizing
Neurobiological
• Neurodegeneration
• Maladaptive
plasticity
Injury
Genetics
• Peripheral and central
sensitization
• Mechanical
• Mutations
• Gene products
Nociceptive Modulation
Pain Management
Education for Abdominal Pain
• The goal of education is to communicate information to
patients and families about abdominal pain and its
connection with psychological triggers, as well as factors
that may exacerbate pain, such as social reinforcement
and school/work avoidance
• Family therapy targets family interactions and
relationships rather than the individual patient in order
to change maladaptive behaviors, increase tolerance of
symptoms and encourage independent coping skills.
Brent M JPGN 2009; Bursch JPGN 2008; Walker Pain 2006;
Chiou & Nurko, 2010
Education: Offering a Validated Explanatory Model for Pain
Cognitive Behavior Therapy (CBT) for Pain
• CBT has most empirical support for treating depression
and anxiety in adults with IBD
• CBT alters behavior, perception, and thinking to change
mood and sensations
• CBT helps individuals to interrupt automatic emotional
processing which maintains negative cognitions and
rumination about pain
• CBT teaches problem-solving skills based on personal
control and the ability to adjust behavior and thoughts
accordingly = stress management
Palsson & Whitehead, 2013
Cognitive Behavioral Therapy versus medical
treatment as usual for depressed adolescents with IBD
• Improved abdominal
pain
Changes in Somatic Symptoms:
CBT vs TAU
****
50
% Change in CDI Item Scores
• CBT modified to target
illness perception and
relaxation for pain
Results
• 3 month pre- post
treatment:
• Decreased depression
• Improved quality of life
40
30
**
**
*
*
20
*
10
0
Anhedonia Sleep problems
PASCET-PI
TAU
Fatigue
Poor appetite
Pain
CDI Items
Szigethy et al., 2004,2007,2009
Definition of Clinical Hypnosis
•
A state of inner absorption,
concentration and focused
attention
• An altered state of consciousness
with observable brain changes.
• This “trance” allows access to
primitive, automatic brain
mechanisms to control perception,
memory and somatic function.
• Utilizes the human brain’s natural
tendency to dissociate.
Driving and missed your exit?
…… Trance
Empirical Evidence for Hypnosis for IBS is growing
• GI symptoms- pain, distention, motility
• Rectal smooth muscle tone/sensitivity
• Analgesic medicine use
• Autonomic nervous system
• Suffering- anxiety, depression, emotional awareness (CNS)
• Quality of life
• Functioning- work productivity, doctor visits
Palsson & Whitehead, 2013
Hypnosis for IBD
Adults
• Improved IBD activity and circulating cytokines
• Improved quality of life
• Less corticosteroid use
• Decreased rectal mucosal release of substance P, histamine
• Decreased rectal blood flow
• Maintaining remission in UC patients
Children
• Improved post-hypnosis in pain, diarrhea, inflammatory markers
• Controlled for change in medical treatment
Miller & Whorwell 2008, Mawdsley 2008
Shaol 2008; Keefer , 2013)
Common elements in empirically tested GI hypnosis
• Brief and time-limited therapy (6-12 weekly or bi-weekly
sessions)
• Interventions are gut-focused: Gastrointestinal suggestions
and gut imagery and metaphors targeting central symptoms
of each disorder, and promoting normalization of gut
functioning and reduced symptom experience.
• Home practice used in between therapist visits with
recorded hypnosis audio exercise or self-hypnosis
Examples of hypnotic language
• “Your brain is now sending
messages to the gut-control
stations to tune down the
intensity and quality of pain
signals so that you feel less
discomfort…”
• “…your brain can easily and
automatically filter out any
uncomfortable sensations and
allow in (warm, cool)
comfortable sensations
Benefits of Psychological Treatment
 High response rate (about 70%)
 Can benefit patients not responding to medical
treatments
 Is additive to and possibly synergistic with
medical treatments
 No side effects
 Benefits continue years after treatment ends
 Reduces health care costs
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Pain Management: Medications
• IBD Medications- remission is goal
• Antispasmodics – beware of obstruction
• NSAIDS and COX-2 inhibitors- beware of worsening
IBD flare
• Acetaminophen- no significant anti-inflammatory,
gastric or renal effects but hepatotoxicity
• Opioids- beware of long-term use
• Psychotropics- do they work?
Srinath et al.; 2012; Grover & Drossman IBD Monitor, 2009
Rationale for Antidepressants for IBD
 Treatment of psychiatric co-morbidity
 Peripheral effects
Motility / secretion
Afferent
 Central pain modulatory effects
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Antidepressants: TCA, SSRI, SNRI
• The neurochemicals targeted
involved in visceral motility and
sensation (IBS).
• Unclear whether they directly
impact nociception or their
beneficial effects are mediated
by decreasing anxiety and
depression.
• SSRI/SNRI: Few side effects or
drug-drug interactions
Mikocka-Walus BMC Gastroenterol 2007, 2009;
Friedrich et. al. Clin. Ther. 2010 ; Rahimi 2009
Tricyclic Antidepressants (TCA)
• Increase serotonin, endogenous opioid release, direct
action on opioid receptors. Potentiate the actions of
opiates requiring lower dose.
• Effects on pain reduction and improved sleep more rapid
than antidepressant effect (3-7 days) and at lower doses.
• Anticholinergic side effects such as dry mouth,
constipation, blurred vision, urinary retention, confusion,
delirium.
• Autonomic side effects include orthostatic hypotension,
sweating, palpitations, tachycardia, increased blood
pressure and prolonged QT, QRS and PR intervals and
depressed ST segments requiring EKG monitoring.
Overall Forest Plot of Antidepressant Studies for IBS
Tricyclic Antidepressants (TCAs)
Treatment Control
Heefner, 1978
Myren, 1982
Ngain, 1984
Boerner, 1988
Bergmann, 1981
Vil, 1991
Drossman, 2003
Talley, 2008
Vahedi, 2008
Subtotal (95% CI)
n/N
n/N
10/22
5/30
14/21
16/42
5/19
14/25
60/115
0/18
8/27
319
12/22
10/31
21/21
19/41
14/16
20/25
36/37
5/16
16/27
256
0.1 0.2
RR (random)
Weight
RR (random)
95% CI
%
95% CI
5.94
2.66
14.74
7.63
3.82
10.67
16.77
0.33
5.02
67.36
0.5
Favors treatment
1
0.83
0.52
0.67
0.82
0.30
0.70
0.83
0.08
0.50
0.68
(0.46,
(0.20,
(0.49,
(0.30,
(0.14,
(0.47,
(0.63,
(0.00,
(0.26,
(0.56,
1.51)
1.33)
0.90)
1.36)
0.65)
1.04)
1.08)
1.36)
0.97)
0.83)
2
10
5
Favors control
Total events: 32 treatments; 153 controls
Test for heterogeneity: Chi2=10.94, df=8, (P=0.21), F=26.9%
Test for overall effect: Z=3.86 (P=0.0001)
Ford AC et al. Gut, Nov 2008; doi:10.1136/gut.2008.163162
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Antidepressant Receptor Site Effects
TCAs (25-150 mg)
Amitriptyline (3o)
Doxepin (3o)
Desipramine (2o)
Nortriptyline (2o)
SSRIs (1-2 pills)
Citalopram
Escitalopram
Fluoxetine
Paroxetine
Sertraline
SNRI’s (variable)
Venlafaxine
Duloxetine
Milnacipran
NE
5HT
Histamine
Ach
+++
++
+++
+++
+++
+++
+++
+
++++
++++
+
++
++++
++
+
++
nil
nil
nil
nil
nil
++++
++++
++++
++++
++++
nil
nil
nil
nil
nil
nil
nil
nil
nil
nil
++
+++
+++
++
+++
++
nil
nil
nil
nil
nil
nil
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Antidepressant considerations
TCA
SSRI
SNRI
Potential benefits
Pain
Depression
Pain
Depression
Anxiety
Pain
Depression
Adverse effects
Sedation
Constipation
Hypotension
Dry mouth
Arrhythmia
Weight gain
Agitation
Diarrhea
Night sweats
Headache
Sexual dysfunction
Nausea
Agitation
Dizziness
Sleep disturbance
Fatigue
Liver dysfunction
Overdose Risk
Moderate
Minimal
Minimal
Cost/month
$5-30
$40-80
$60-100
Approach to prescribing antidepressants
• Address false expectations or beliefs of patients
• Provide psychopathological explanation of patient’s
symptoms that psychopharmacological agent would
target
• Provide information/rationale aligned with patient’s
interests/concerns
• Negotiate treatment plan
– Benefit in 4-6 weeks
– Most side effects decrease in 1-2 weeks
– Consider previous drugs that works and family history of drug
response
Drossman 2002
Gabapentin/pregabalin
• Centrally acting agents with mechanism unclear.
– ?centrally acting voltage-gated calcium channel modulators.
– structurally similar to γ-amino butyric acid (GABA), which is
a major inhibitory neurotransmitter in the CNS.
• They reduce neuropathic pain by attenuating the
release of many different neurotransmitters
• Has few side effects and does not require serum
monitoring.
Taylor 2007; Gale & Houghton, 2011;
Richard 2013
Other Central Agents with GI effects
 Mirtazapine
 Serotonergic and noradrenergic drug with 5HT2 and
effects – can have pain benefit
Use with nausea, anorexia, weight loss, diarrhea
Some sedation
5HT3
 Clonidine
α2-adrenergic against with central (anxiety reduction)
peripheral (pain reduction via bowel compliance)
Helps reduce diarrhea
Prevents adrenergic effects of narcotic withdrawal
and
 Buspirone
Azapirone with anti-anxiety effects acting on non BZD
GABA receptors
Has 5HT1 and 5HT2 effects
Potential benefit for PDS (dyspepsia) due to receptive
relaxation of stomach
2061
 Quetiapine
Atypical antipsychotic with complex effects
Dopamine (D1 and D2) and Serotonin (5HT1a and 5HT2)
antagonism with some α2-adrenergic blocking effect
Treatment Effects
Bipolar disorder and schizophrenia (labelling)
Augmentation for OCD, PTSD, depression
Sleep (normal sleep architecture)
Anxiety reduction
Some analgesic benefit
Improves painful FBD refractory to TCA or SNRI1
Side effects
Sedation, somnolence, dry mouth
Metabolic syndrome (weight gain, glucose intolerance,
hyperlipidemia)
Abnormal LFTs (rare)
1Grover
M, Drossman DA. Dig Dis Sci 2009;54:1284
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Atypical Antipsychotic Quetiapine*
in Refractory FGIDs
10/21 (48%) subjects discontinued Quetiapine
90
Significantly/somewhat better
Same
Worse
80
70
60
%
50
Patient
response 40
30
20
10
0
Global GI
symptoms
Abdominal
pain
Bowel
habits
* Dopamine (D1 and D2) and Serotonin (5HT1A and 5HT2) antagonism with some a2-adrenergic blocking effect
Grover M, Drossman DA, et al. Dig Dis Sci 2009; 54:1284
2787
Potential Benefits of Supplemental
Psychopharmacologic Agents
CENTRAL ACTING
• Central pain perception—
analgesia
PERIPHERAL ACTING
• Peripheral analgesic effects—
alters visceral afferent signaling
•
• GI physiology (motility and
secretion) via effects on
neurotransmitter pathways
Mood—anxiety, increased
stress responsiveness
• Treatment of associated
psychiatric disorders—
depression, PTSD, somatization
• Treatment of associated sleep
disturbances
• Smooth muscle effects on
viscera
Grover & Drossman, 2011
Opioids (Narcotics)
• Bind to CNS opioid receptors and inhibit release of
pain neurotransmitters.
• Mixed agonist/antagonists available
• Many side effects –constipation, nausea, vomiting,
sedation, pruritis, respiratory depression.
Opioids (narcotics)
• Used acutely after surgical resection of the intestinal
tract and to treat pain due to inflammation in IBD.
• 5–13% of patients with IBD are on chronic narcotics in
the outpatient setting.
• Risk factors for outpatient narcotic use in IBD include
psychiatric comorbidities (anxiety and depression), history of
abuse, female gender, and a high degree of clinical symptoms
• 20-70% inpatients with IBD use narcotics
• Risk factors for inpatient narcotic use include diagnosis of CD,
substance abuse, psychiatric factors, and the presence of IBS
symptoms
Edwards 2001; Cross 2005; Hanson 2009; Long 2011
Concerns with Opiates
• Psychological/physical
dependence
• Higher rates of
infection/mortality
• Narcotic Bowel Syndrome
(NBS)
Grunkmeier 2007; Lichenstein 2006;
Typical Clinical Presentation for NBS
 Chronic or recurrent abdominal pain which is treated with
narcotics
 Narcotics may have relieved pain initially but then stop
working
 Shorter pain-free periods result in increasing narcotic doses
 Increasing doses further alter motility and aggravate pain
 Can occur with in patients IBS, organic disease or otherwise
health subjects (e.g., post operative)
Grover & Drossman 2009; Long &
Drossman; 2010
Risk of long-term opioid therapy
• Loss of efficacy over time
• Cognitive impairment
• Abnormal pain sensitivity (opioid •
induced hyperalgesia)
•
• Aberrant drug-related behavior
•
• Addiction, abuse and diversion
Constipation
Abnormal immune function
Alterations of the reproductive
system (opioid-induced
testosterone deficiency)
• Increased risk of fracture
Grunkenheimer 2007
Drossman Center
There are safe ways to taper narcotics
under appropriate medical care
Narcotic Withdrawal Protocol
Accept pain as real and treatable
Elicit patients concerns/expectations
Provide information through a dialog
Present the withdrawal program
Gauge the patient’s response
Clonidine 0.1mg PO q 6 hrs.
Lorazepam 1mg PO q 6hrs.
TCA or SNRI
Morphine equiv. Dose (mg)
220 200 180 160 140 120 100
80
60
40
20
0
PEG 3350 17g PO BID
Physician – Patient Relationship
Day of taper
-3
-2
-1
0
1
2
3
4
5
6
7
Grunkemeier, DMS et al., Clin Gastroenterology and Hepatology 2007; 5:1126
8
9
10 . . . 21
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Abdominal Pain Scores
60
50
40
VAS
(0-100)
30
20
10
0
Pre-detoxification
Post-detoxification
Stayed off
narcotics
Went back on
narcotics
n=39
n=37
n=13
n=10
Drossman DA et al. Am J Gastro 2012;107:1426
3 month follow-up
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Relationship of COMM Scores* to
Detoxification and Responder Status
2
1.5
Successful
Successful
Detoxification
detoxification
p<0.06
Responder
Responder
p<0.02
Score 1
0.5
29
4
Yes
No
No. of subjects
20
12
Yes
No
0
* = Higher COMM scores indicates greater drug abuse potential
Drossman DA et al. Am J Gastro 2012;107:1426
2591
Pain Management: Other therapies
• Exercise
• Complimentary alternative medicine (CAM)
– Acupuncture
– Yoga
– Massage
– Meditation
• Support groups
Acupuncture
• Postulated to have effects on acid secretion, GI motility and pain
sensation via release of opiates in brain and body
• Adults with IBS- no difference to sham procedure
• Children with IBS or IBD- no support
• Greater impact than placebo in children with chronic
constipation
Schneider Gut 2006; Lembo Am J Gastroenterol
2009; Broide Dig Dis Sci 2001
Summary Points
• IBD is associated with psychopathology, functional pain,
and maladaptive stress responses that increase morbidity,
suffering, and costs.
• Maximize treatment of underlying inflammation.
• Integrated, personalized behavioral interventions to improve
coping and decrease psychopathology can impact medical
outcomes.
• Pain medications as second line therapy
• Better identification of risk factors for psychological stress
can lead to prevention strategies.
The Drossman Center for the
Education and Practice of
Biopsychosocial Care
Focused on improving healthcare by improving
doctor-patient communications. With the
DrossmanCare training, healthcare providers
learn how to better communicate with patients
to improve satisfaction and clinical outcomes.
www.drossmancenter.com
drossmangastroenterology.com
Augumentation Therapy
● Two different antidepressants
● Antidepressant + non-pharmacological Rx
● Antidepressant + atypical antipsychotic
● Antidepressant + anticholinergic
● Antidepressant + Pregabalin or Gabapentin
Dynamicinterpersonal
psycho Rx
Cognitive
behavioral Rx
Hypnosis
Antidepressants
Nonpharmacologic
Rx
Symptomatic
Rx
Pharmacologic
Rx
Patient-physician
Therapeutic relationship
Sperber A and Drossman D, Alim Pharm Ther 2011;33:514
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Graded Multi-Component Treatment
+
 Narcotic withdrawal
 Multidisciplinary approach
 Psychological treatments
 Central treatments
 Manage stress
 Gut treatments
+
 Diet, lifestyle advice
 Positive diagnosis
 Explain, reassure
Severe
Moderate
Mild
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